Neuron's new discovery of the mechanism of early drug addiction formation

Responsible editor | Dopamine is the main neurotransmitter of the reward system in the brain.
The dopamine signal transmission in the striatum (DSt) and nucleus accumbens (NAc) plays a central role in regulating learning and goal-oriented behavior
.

The dysfunction of these circuits caused by drug abuse is considered to be the key to addiction
.

Early studies on cocaine addicted humans and non-human primates using positron emission tomography (PET) found that the reduced availability of dopamine receptors (especially D2 receptors) was associated with cocaine (cocaine).
) Abuse related
.

In addition, studies that genetically or virally alter the expression of dopamine D2 receptors in rodents have shown that the reduction of D2 receptor (D2R) levels may be a key consequence of cocaine exposure and addiction-related causal behaviors
.

However, the limitation of this work is that neuroimaging (PET) studies cannot determine whether the decrease in D2 receptor availability is due to changes in D2 receptor expression, or due to D2 receptor localization, transport, sensitivity, or downstream signals.
Due to changes in efficacy
.

 On September 9, 2021, the Christopher Ford team from Colorado Anschutz School of Medicine and Case Western Reserve University School of Medicine (the first author is Sheng Gong) published in Neuron magazine entitled Cocaine Shifts dopamine D2 receptor sensitivity to gate conditioned behaviors Research papers
.

In this paper, the author studied how cocaine modulates the sensitivity of D2 receptors in D2-medium spiny neuron cells (D2-MSNs), and found that cocaine can dynamically regulate the expression of G protein to affect the sensitivity of D2 receptors
.

 In order to detect the sensitivity of the D2 receptor, the authors used viral methods to express the Kir3/GIRK family potassium channel (GIRK) linked by the Gα(i/o) protein
.

The authors found that cocaine exposure did not change the expression of D2 receptors in the nucleus accumbens, but changed the efficacy of D2 receptor signaling and the sensitivity of D2 receptors to dopamine
.

Western blotting to detect the expression of G protein showed that the nucleus accumbens D2 receptor is more sensitive than the striatum because there is a large amount of Gα(o) in the nucleus accumbens than the striatum
.

Cocaine can reduce the expression of Gα(o) protein in the nucleus accumbens, thereby reducing the sensitivity of D2 receptors
.

Further research found that changes in D2 receptor sensitivity are sufficient to cause specific addictive behaviors caused by cocaine exposure
.

A series of behavioral studies such as cocaine self-administration, conditioned spatial preference, and behavioral sensitization studies.
The author's research shows that the decrease in D2 receptor sensitivity caused by psychostimulants drives cocaine-seeking behavior
.

In order to further study how cocaine regulates brain pathways to reduce D2 receptor sensitivity, the author used a series of studies such as in vivo pharmacology, chemogenetic, and gene editing methods (CRISPR-Cas9) to find that cocaine The resulting increase in dopamine levels can directly stimulate the D1 receptor (D1R) in the medial prefrontal cortex (mPFC) cells.
D1 receptor activation can promote the release of glutamate in the nucleus accumbens, thereby activating the N-methyl group in D2-MSNs -Aspartate receptor (NMDAR), which further reduces the sensitivity of D2 receptors
.

This work fills a key gap in understanding how chronic drug abuse alters dopamine receptor signaling in a region-specific manner
.

Although the work of many molecular pharmacology laboratories has shown that many factors regulate different aspects of GPCR signaling in expression systems, little is known about how these factors regulate endogenous receptor signaling in neurons
.

By elucidating the factors that regulate D2 receptor sensitivity and the changes caused by cocaine, this work provides new insights into key changes in the basis of addiction
.

Secondly, and more importantly, this work has also identified a new and highly druggable therapeutic target for the treatment of addiction and other drug abuse disorders
.

Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
08.
012 Reprinting instructions [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights , The offender must be investigated
.